1. Field of the Invention
The present invention relates to pharmaceutical preparations of biologically active peptides and proteins suitable for enteral administration.
2. Description of the Prior Art
As a result of recent progress in the field of biochemistry, many biologically active peptides and proteins are now available for clinical use. However, because they are proteins of low lipophilicity and can be destroyed in the gastrointestinal tract by enzymes capable of cleaving peptide bonds and in the stomach by acid hydrolysis, methods of administering these compounds orally have not kept pace with their synthesis and identification. Typical of this situation is the case of insulin. It has long been established that insulin is an effective endogenous hormone useful in the treatment of diabetes mellitus. Furthermore, the intact insulin molecule is known to pass through the intestinal wall of various animals under specified conditions. However, adult animals (including humans) absorb insulin poorly when it is orally administered. This is probably due to a combination of factors: destruction of intact insulin molecules as previously discussed and slow passage of intact insulin molecules through the intestinal wall because of low lipophilicity. Consequently, therapeutic use of insulin is limited by the necessity of administering it parenterally, particularly by intravenous or intramuscular injection.
The desire to avoid parenteral administration of insulin has stimulated research efforts in other modes of administration, among which oral administration is the most attractive. Although efforts have been made to develop oral hypoglycemic agents other than insulin, a great deal of effort has also been concentrated on the modification of insulin in such a way that an immunologically intact and metabolically competent insulin molecule can be absorbed through the intestine so that insulin itself or a derivative thereof may be orally administered. The search in this area has been concentrated in three directions: the development of adjuvants, the co-administration of enzymatic inhibitors, and the development of liposomes. Adjuvants used with insulin include resorcinols, non-ionic surfactants such as polyoxyethylene oleyl ether, and n-hexadecyl polyethylene ether. Enzyme inhibitors include pancreatic trypsin inhibitor, diisopropylfluorophosphate (DFP), and trasylol. Liposomes include water-in-oil-in-water insulin emulsions as well as conventional liposomes.
The co-administration of enzyme inhibitors has had some degree of success, particularly when used with duodenal administration. Adjuvants such as hexylresorcinol have been administered with insulin to diabetic patients to give systemic, hypoglycemic effects. However, some adjuvants are limited to successful intra-jejunal administration. Compared to the other types of oral insulin preparations, liposomes have been relative successful. Several studies have shown systemic, hypoglycemic effects after administration of a liposome containing insulin (e.g., Patel et al, FEBS Letters, 62, 60 (1976); Hashimoto et al, Endocrinol., Japan, 26, 337 (1979)). However, liposomes are still in the development stage of their use as oral hypoglycemic agents and face continued problems of stability, shelf-life, and so forth.
The difficulties of preparing other peptide and protein hormones (and other biologically active peptides and proteins) for oral ingestion or other types of enteral administration parallel the problems associated with insulin. Accordingly, there remains a need for a composition generally capable of effecting the oral administration of biologically active peptides and proteins.